Biological Diversity from a Structurally Diverse Library: Systematically Scanning Conformational Space Using a Pyranose Scaffold
Author(s)
Abbenante, Giovanni
Becker, Bernd
Blanc, Sebastien
Clark, Chris
Condie, Glenn
Fraser, Graeme
Grathwohl, Matthias
Halliday, Judy
Henderson, Senka
Lam, Ann
Liu, Ligong
Mann, Maretta
Muldoon, Craig
Pearson, Andrew
Premraj, Rajaratnam
Ramsdale, Trade
Rossetti, Tony
Schafer, Karl
Le Thanh, Giang
Tometzki, Gerald
Vari, Frank
Verquin, Geraldine
Waanders, Jennifer
West, Michael
Wimmer, Norbert
Yau, Annika
Zuegg, Johannes
Meutermans, Wim
Griffith University Author(s)
Year published
2010
Metadata
Show full item recordAbstract
Success in discovering bioactive peptide mimetics is often limited by the difficulties in correctly transposing known binding elements of the active peptide onto a small and metabolically more stable scaffold while maintaining bioactivity. Here we describe a scanning approach using a library of pyranose-based peptidomimetics that is structurally diverse in a systematic manner, designed to cover all possible conformations of tripeptide motifs containing two aromatic groups and one positive charge. Structural diversity was achieved by efficient selection of various chemoforms, characterized by a choice of pyranose scaffold of ...
View more >Success in discovering bioactive peptide mimetics is often limited by the difficulties in correctly transposing known binding elements of the active peptide onto a small and metabolically more stable scaffold while maintaining bioactivity. Here we describe a scanning approach using a library of pyranose-based peptidomimetics that is structurally diverse in a systematic manner, designed to cover all possible conformations of tripeptide motifs containing two aromatic groups and one positive charge. Structural diversity was achieved by efficient selection of various chemoforms, characterized by a choice of pyranose scaffold of defined chirality and substitution pattern. A systematic scanning library of 490 compounds was thus designed, produced, and screened in vitro for activity at the somatostatin (sst1-5) and melanin-concentrating hormone (MCH1) receptors. Bioactive compounds were found for each target, with specific chemoform preferences identified in each case, which can be used to guide follow-on drug discovery projects without the need for scaffold hopping.
View less >
View more >Success in discovering bioactive peptide mimetics is often limited by the difficulties in correctly transposing known binding elements of the active peptide onto a small and metabolically more stable scaffold while maintaining bioactivity. Here we describe a scanning approach using a library of pyranose-based peptidomimetics that is structurally diverse in a systematic manner, designed to cover all possible conformations of tripeptide motifs containing two aromatic groups and one positive charge. Structural diversity was achieved by efficient selection of various chemoforms, characterized by a choice of pyranose scaffold of defined chirality and substitution pattern. A systematic scanning library of 490 compounds was thus designed, produced, and screened in vitro for activity at the somatostatin (sst1-5) and melanin-concentrating hormone (MCH1) receptors. Bioactive compounds were found for each target, with specific chemoform preferences identified in each case, which can be used to guide follow-on drug discovery projects without the need for scaffold hopping.
View less >
Journal Title
Journal of Medicinal Chemistry
Volume
53
Issue
15
Copyright Statement
Self-archiving of the author-manuscript version is not yet supported by this journal. Please refer to the journal link for access to the definitive, published version or contact the authors for more information.
Subject
Medicinal and biomolecular chemistry
Biomolecular modelling and design
Cheminformatics and quantitative structure-activity relationships
Organic chemistry
Organic chemical synthesis
Pharmacology and pharmaceutical sciences